Related Experiment Video
Updated: Aug 19, 2026
Implantation and Monitoring by PET/CT of an Orthotopic Model of Human Pleural Mesothelioma in Athymic Mice
Published on: December 21, 2019
Farnesyltransferase inhibitors and human malignant pleural mesothelioma: a first-step comparative translational study
Alfredo Cesario1, Alessia Catassi, Luigi Festi
1Department of Surgical Science, Division of General Thoracic Surgery, Catholic University, Rome, Italy.
Abstract:
It is known that the potential clinical use of farnesyltransferase inhibitors (FTI) could be expanded to include cancers harboring activated receptor tyrosine kinases. Approximately 70% of malignant pleural mesotheliomas (MPM) overexpress epidermal growth factor receptors (EGFR) and a subset express both EGFR and transforming growth factor alpha (TGF-alpha), suggesting an autocrine role for EGFR in MPM. We checked on MPM cells (10 human cell lines, 11 primary cultures obtained by human biopsies, and 7 short-term normal mesothelial cell cultures) concerning the following: (a) the relative overexpression of EGFR (Western blotting, flow cytometry, immunohistochemistry), (b) the relative expression of EGFR ligands (EGF, amphiregulin, TGF-alpha, ELISA), (c) the relative increase of the activated form of Ras (Ras-bound GTP) after EGF stimulation (Ras activation assay), (d) the efficacy of five different FTIs (HDJ2 prenylation, cell cytotoxicity, and apoptosis using ApopTag and gel ladder). EGFR was overexpressed in MPM cells compared with normal pleural mesothelial cells in equivalent levels as in non-small cell lung cancer cells A459. MPM cells constitutively expressed EGFR ligands; however, Ras activation was attenuated at high EGF concentrations (100 ng/mL). Growth of MPM cells was substantially not affected by treatment with different FTIs (SCH66336, BMS-214662, R115777, RPR-115135, and Manumycin). Among these, BMS-214662 was the only one moderately active. BMS-214662 triggered apoptosis in a small fraction of cells (not higher than 30%) that was paralleled by a slight decrease in the levels of TGF-alpha secreted by treated MPM cells. Our data highlighted the concept that the same signaling pathway can be regulated in different ways and these regulations can differ between different cells of different origin.
Insights
Farnesyltransferase inhibitors (FTI) showed limited efficacy in treating malignant pleural mesothelioma (MPM) despite EGFR overexpression. BMS-214662 moderately induced apoptosis in MPM cells, suggesting complex signaling pathway regulation.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Malignant pleural mesothelioma (MPM) often overexpresses epidermal growth factor receptors (EGFR).
- EGFR signaling is implicated in MPM pathogenesis, suggesting potential therapeutic targets.
Purpose of the Study:
- To investigate the efficacy of farnesyltransferase inhibitors (FTIs) in MPM.
- To evaluate EGFR and ligand expression, Ras activation, and FTI effects on MPM cell lines and primary cultures.
Main Methods:
- Western blotting, flow cytometry, and immunohistochemistry for EGFR expression.
- ELISA for EGFR ligands.
- Ras activation assays.
- Cell cytotoxicity and apoptosis assays for five different FTIs.
Main Results:
- MPM cells overexpressed EGFR compared to normal mesothelial cells.
- MPM cells expressed EGFR ligands, but Ras activation was attenuated at high EGF concentrations.
- FTIs showed minimal impact on MPM cell growth; BMS-214662 moderately induced apoptosis and decreased TGF-alpha secretion.
Conclusions:
- FTIs have limited efficacy in MPM despite EGFR overexpression.
- MPM signaling pathways are complex and differentially regulated.
- BMS-214662 shows modest activity, warranting further investigation in specific MPM contexts.
